Human hepatocyte growth factor down-regulates the expression of cytochrome P450 isozymes in human hepatocytes in primary culture.
This study examines the effects of recombinant human hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, on the cytochrome P450 (CYP) system and conjugating reactions in cultured human hepatocytes. The time course of HGF effects on CYP1A1/2 (7-ethoxyresorufin O-deethylase) activity revealed that maximal inhibition was observed at 96 hr of culture. HGF produced a general decrease in the activity of all the CYP isozymes studied, namely CYP1A1/2 (7-ethoxyresorufin O-deethylase), CYP2B6 (7-benzoxyresorufin O-debenzylase), CYP2A6 (coumarin 7-hydroxylase), CYP2E1 (p-nitrophenol hydroxylase) and CYP3A4 (testosterone 6beta-hydroxylase). In contrast, UDP-glucuronyltransferase and glutathione S-transferase activities and reduced glutathione levels were not modified significantly by the factor. When hepatocytes were treated with inducers, marked increases in the specific activities of CYP1A1/2 by 3-methylcholanthrene and CYP3A4 by rifampicin were observed, and these inductive effects were greatly reduced in the presence of HGF. Furthermore, CYP1A2 and CYP3A4 protein levels also dropped in the presence of HGF both in control and induced hepatocytes. The observed changes in the activity and protein levels of CYP1A2 and CYP3A4 correlated with a reduction in the specific messenger RNA levels both in control, 3-methylcholanthrene-treated (for CYP1A2) and rifampicin-treated (for CYP3A4) hepatocytes, which thus suggested that HGF could down-regulate CYP expression at a pretranslational level.
Donato
M T
MT
Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain.
Gómez-Lechón
M J
MJ
Jover
R
R
Nakamura
T
T
Castell
J V
JV
D000209:Acute-Phase Proteins / Q000096:biosynthesis; D000293:Adolescent; D000368:Aged; D001711:Biotransformation / Q000187:drug effects*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D000209:Acute-Phase Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005978:Glutathione